Optometry and Vision Sciences - Research Publications

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    Systematic review and appraisal of quality, definitions and treatment recommendations of clinical guidelines for glaucoma suspects
    Wu, Z ; Karunaratne, S ; Ang, GS ; Martin, KR ; Downie, LE (WILEY, 2023-12-13)
    BACKGROUND: To appraise the quality of clinical practice guidelines for glaucoma suspects, and to assess their consistency for how a 'glaucoma suspect' is defined and their recommendations for treatment initiation for such individuals. METHODS: This study included all documents that self-identified as a 'guideline' and provided recommendation(s) for the clinical care of glaucoma suspects. The quality of eligible guidelines was assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. RESULTS: From 1196 records retrieved from comprehensive searches and two records manually included, 20 clinical practice guidelines were deemed eligible. Based on an appraisal using the AGREE II instrument, 16 (80%) guidelines had ≤2 domains with scores >66%. Overall, the lowest scoring domains were for applicability, editorial independence and stakeholder involvement. There was relatively poor agreement across the guidelines for what defines a 'glaucoma suspect' or 'primary open angle glaucoma [POAG] suspect', as well as the recommendations and criteria for treatment initiation in these populations. There was better agreement for the definition and recommendations for treatment initiation for 'primary angle closure suspects'. CONCLUSIONS: There is substantial room to improve the methodological quality of most current international clinical guidelines for glaucoma suspects. Clinicians should consider this finding when using such guidelines to inform their care of glaucoma suspects. Substantial variation in the definition of a POAG suspect and recommendations for treatment initiation underscores important gaps in the current evidence for the accurate prediction of glaucoma development and treatment effectiveness in these individuals.
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    Preexisting immunity restricts mucosal antibody recognition of SARS-CoV-2 and Fc profiles during breakthrough infections
    Selva, KJ ; Ramanathan, P ; Haycroft, ER ; Reynaldi, A ; Cromer, D ; Tan, CW ; Wang, L-F ; Wines, BD ; Hogarth, PM ; Downie, LE ; Davis, SK ; Purcell, RA ; Kent, HE ; Juno, JA ; Wheatley, AK ; Davenport, MP ; Kent, SJ ; Chung, AW (AMER SOC CLINICAL INVESTIGATION INC, 2023-09-22)
    Understanding mucosal antibody responses from SARS-CoV-2 infection and/or vaccination is crucial to develop strategies for longer term immunity, especially against emerging viral variants. We profiled serial paired mucosal and plasma antibodies from COVID-19 vaccinated only vaccinees (vaccinated, uninfected), COVID-19-recovered vaccinees (recovered, vaccinated), and individuals with breakthrough Delta or Omicron BA.2 infections (vaccinated, infected). Saliva from COVID-19-recovered vaccinees displayed improved antibody-neutralizing activity, Fcγ receptor (FcγR) engagement, and IgA levels compared with COVID-19-uninfected vaccinees. Furthermore, repeated mRNA vaccination boosted SARS-CoV-2-specific IgG2 and IgG4 responses in both mucosa biofluids (saliva and tears) and plasma; however, these rises only negatively correlated with FcγR engagement in plasma. IgG and FcγR engagement, but not IgA, responses to breakthrough COVID-19 variants were dampened and narrowed by increased preexisting vaccine-induced immunity against the ancestral strain. Salivary antibodies delayed initiation following breakthrough COVID-19 infection, especially Omicron BA.2, but rose rapidly thereafter. Importantly, salivary antibody FcγR engagements were enhanced following breakthrough infections. Our data highlight how preexisting immunity shapes mucosal SARS-CoV-2-specific antibody responses and has implications for long-term protection from COVID-19.
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    Mucosal antibody responses following Vaxzevria vaccination
    Selva, KJ ; Ramanathan, P ; Haycroft, ER ; Tan, CW ; Wang, L-F ; Downie, LE ; Davis, SK ; Purcell, RA ; Kent, HE ; Juno, JA ; Wheatley, AK ; Davenport, MP ; Kent, SJ ; Chung, AW (WILEY, 2023-11)
    Mucosal antibodies play a key role in protection against breakthrough COVID-19 infections and emerging viral variants. Intramuscular adenovirus-based vaccination (Vaxzevria) only weakly induces nasal IgG and IgA responses, unless vaccinees have been previously infected. However, little is known about how Vaxzevria vaccination impacts the ability of mucosal antibodies to induce Fc responses, particularly against SARS-CoV-2 variants of concern (VoCs). Here, we profiled paired mucosal (saliva, tears) and plasma antibodies from COVID-19 vaccinated only vaccinees (uninfected, vaccinated) and COVID-19 recovered vaccinees (COVID-19 recovered, vaccinated) who both received Vaxzevria vaccines. SARS-CoV-2 ancestral-specific IgG antibodies capable of engaging FcγR3a were significantly higher in the mucosal samples of COVID-19 recovered Vaxzevria vaccinees in comparison with vaccinated only vaccinees. However, when IgG and FcγR3a engaging antibodies were tested against a panel of SARS-CoV-2 VoCs, the responses were ancestral-centric with weaker recognition of Omicron strains observed. In contrast, salivary IgA, but not plasma IgA, from Vaxzevria vaccinees displayed broad cross-reactivity across all SARS-CoV-2 VoCs tested. Our data highlight that while intramuscular Vaxzevria vaccination can enhance mucosal antibodies responses in COVID-19 recovered vaccinees, restrictions by ancestral-centric bias may have implications for COVID-19 protection. However, highly cross-reactive mucosal IgA could be key in addressing these gaps in mucosal immunity and may be an important focus of future SARS-CoV-2 vaccine development.
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    Redefining the human corneal immune compartment using dynamic intravital imaging
    Downie, LE ; Zhang, X ; Wu, M ; Karunaratne, S ; Loi, JK ; Senthil, K ; Arshad, S ; Bertram, K ; Cunningham, AL ; Carnt, N ; Mueller, SN ; Chinnery, HR (NATL ACAD SCIENCES, 2023-08-01)
    The healthy human cornea is a uniquely transparent sensory tissue where immune responses are tightly controlled to preserve vision. The cornea contains immune cells that are widely presumed to be intraepithelial dendritic cells (DCs). Corneal immune cells have diverse cellular morphologies and morphological alterations are used as a marker of inflammation and injury. Based on our imaging of corneal T cells in mice, we hypothesized that many human corneal immune cells commonly defined as DCs are intraepithelial lymphocytes (IELs). To investigate this, we developed functional in vivo confocal microscopy (Fun-IVCM) to investigate cell dynamics in the human corneal epithelium and stroma. We show that many immune cells resident in the healthy human cornea are T cells. These corneal IELs are characterized by rapid, persistent motility and interact with corneal DCs and sensory nerves. Imaging deeper into the corneal stroma, we show that crawling macrophages and rare motile T cells patrol the tissue. Furthermore, we identify altered immune cell behaviors in response to short-term contact lens wear (acute inflammatory stimulus), as well as in individuals with allergy (chronic inflammatory stimulus) that was modulated by therapeutic intervention. These findings redefine current understanding of immune cell subsets in the human cornea and reveal how resident corneal immune cells respond and adapt to chronic and acute stimuli.
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    Blue-light filtering spectacle lenses for visual performance, sleep, and macular health in adults (Review)
    Singh, S ; Keller, PR ; Busija, L ; McMillan, P ; Makrai, E ; Lawrenson, JG ; Hull, CC ; Downie, LE (WILEY, 2023)
    BACKGROUND: 'Blue-light filtering', or 'blue-light blocking', spectacle lenses filter ultraviolet radiation and varying portions of short-wavelength visible light from reaching the eye. Various blue-light filtering lenses are commercially available. Some claims exist that they can improve visual performance with digital device use, provide retinal protection, and promote sleep quality. We investigated clinical trial evidence for these suggested effects, and considered any potential adverse effects. OBJECTIVES: To assess the effects of blue-light filtering lenses compared with non-blue-light filtering lenses, for improving visual performance, providing macular protection, and improving sleep quality in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; containing the Cochrane Eyes and Vision Trials Register; 2022, Issue 3); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and WHO ICTRP, with no date or language restrictions. We last searched the electronic databases on 22 March 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs), involving adult participants, where blue-light filtering spectacle lenses were compared with non-blue-light filtering spectacle lenses. DATA COLLECTION AND ANALYSIS: Primary outcomes were the change in visual fatigue score and critical flicker-fusion frequency (CFF), as continuous outcomes, between baseline and one month of follow-up. Secondary outcomes included best-corrected visual acuity (BCVA), contrast sensitivity, discomfort glare, proportion of eyes with a pathological macular finding, colour discrimination, proportion of participants with reduced daytime alertness, serum melatonin levels, subjective sleep quality, and patient satisfaction with their visual performance. We evaluated findings related to ocular and systemic adverse effects. We followed standard Cochrane methods for data extraction and assessed risk of bias using the Cochrane Risk of Bias 1 (RoB 1) tool. We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included 17 RCTs, with sample sizes ranging from five to 156 participants, and intervention follow-up periods from less than one day to five weeks. About half of included trials used a parallel-arm design; the rest adopted a cross-over design. A variety of participant characteristics was represented across the studies, ranging from healthy adults to individuals with mental health and sleep disorders. None of the studies had a low risk of bias in all seven Cochrane RoB 1 domains. We judged 65% of studies to have a high risk of bias due to outcome assessors not being masked (detection bias) and 59% to be at high risk of bias of performance bias as participants and personnel were not masked. Thirty-five per cent of studies were pre-registered on a trial registry. We did not perform meta-analyses for any of the outcome measures, due to lack of available quantitative data, heterogenous study populations, and differences in intervention follow-up periods. There may be no difference in subjective visual fatigue scores with blue-light filtering lenses compared to non-blue-light filtering lenses, at less than one week of follow-up (low-certainty evidence). One RCT reported no difference between intervention arms (mean difference (MD) 9.76 units (indicating worse symptoms), 95% confidence interval (CI) -33.95 to 53.47; 120 participants). Further, two studies (46 participants, combined) that measured visual fatigue scores reported no significant difference between intervention arms. There may be little to no difference in CFF with blue-light filtering lenses compared to non-blue-light filtering lenses, measured at less than one day of follow-up (low-certainty evidence). One study reported no significant difference between intervention arms (MD - 1.13 Hz lower (indicating poorer performance), 95% CI - 3.00 to 0.74; 120 participants). Another study reported a less negative change in CFF (indicating less visual fatigue) with high- compared to low-blue-light filtering and no blue-light filtering lenses. Compared to non-blue-light filtering lenses, there is probably little or no effect with blue-light filtering lenses on visual performance (BCVA) (MD 0.00 logMAR units, 95% CI -0.02 to 0.02; 1 study, 156 participants; moderate-certainty evidence), and unknown effects on daytime alertness (2 RCTs, 42 participants; very low-certainty evidence); uncertainty in these effects was due to lack of available data and the small number of studies reporting these outcomes. We do not know if blue-light filtering spectacle lenses are equivalent or superior to non-blue-light filtering spectacle lenses with respect to sleep quality (very low-certainty evidence). Inconsistent findings were evident across six RCTs (148 participants); three studies reported a significant improvement in sleep scores with blue-light filtering lenses compared to non-blue-light filtering lenses, and the other three studies reported no significant difference between intervention arms. We noted differences in the populations across studies and a lack of quantitative data. Device-related adverse effects were not consistently reported (9 RCTs, 333 participants; low-certainty evidence). Nine studies reported on adverse events related to study interventions; three studies described the occurrence of such events. Reported adverse events related to blue-light filtering lenses were infrequent, but included increased depressive symptoms, headache, discomfort wearing the glasses, and lower mood. Adverse events associated with non-blue-light filtering lenses were occasional hyperthymia, and discomfort wearing the spectacles. We were unable to determine whether blue-light filtering lenses affect contrast sensitivity, colour discrimination, discomfort glare, macular health, serum melatonin levels or overall patient visual satisfaction, compared to non-blue-light filtering lenses, as none of the studies evaluated these outcomes. AUTHORS' CONCLUSIONS: This systematic review found that blue-light filtering spectacle lenses may not attenuate symptoms of eye strain with computer use, over a short-term follow-up period, compared to non-blue-light filtering lenses. Further, this review found no clinically meaningful difference in changes to CFF with blue-light filtering lenses compared to non-blue-light filtering lenses. Based on the current best available evidence, there is probably little or no effect of blue-light filtering lenses on BCVA compared with non-blue-light filtering lenses. Potential effects on sleep quality were also indeterminate, with included trials reporting mixed outcomes among heterogeneous study populations. There was no evidence from RCT publications relating to the outcomes of contrast sensitivity, colour discrimination, discomfort glare, macular health, serum melatonin levels, or overall patient visual satisfaction. Future high-quality randomised trials are required to define more clearly the effects of blue-light filtering lenses on visual performance, macular health and sleep, in adult populations.
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    TFOS Lifestyle Report Executive Summary: A Lifestyle Epidemic - Ocular Surface Disease
    Craig, JP ; Alves, M ; Wolffsohn, JS ; Downie, LE ; Efron, N ; Galor, A ; Gomes, JAP ; Jones, L ; Markoulli, M ; Stapleton, F ; Starr, CE ; Sullivan, AG ; Willcox, MDP ; Sullivan, DA (ELSEVIER, 2023-10)
    The Tear Film & Ocular Surface Society (TFOS) Workshop entitled 'A Lifestyle Epidemic: Ocular Surface Disease' was a global initiative undertaken to establish the direct and indirect impacts of everyday lifestyle choices and challenges on ocular surface health. This article presents an executive summary of the evidence-based conclusions and recommendations of the 10-part TFOS Lifestyle Workshop report. Lifestyle factors described within the report include contact lenses, cosmetics, digital environment, elective medications and procedures, environmental conditions, lifestyle challenges, nutrition, and societal challenges. For each topic area, the current literature was summarized and appraised in a narrative-style review and the answer to a key topic-specific question was sought using systematic review methodology. The TFOS Lifestyle Workshop report was published in its entirety in the April 2023 and July 2023 issues of The Ocular Surface journal. Links to downloadable versions of the document and supplementary material, including report translations, are available on the TFOS website: http://www.TearFilm.org.
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    Is critical flicker-fusion frequency a valid measure of visual fatigue? A post-hoc analysis of a double-masked randomised controlled trial
    Singh, S ; Downie, LEE ; Anderson, AJJ (WILEY, 2023-03)
    PURPOSE: Critical flicker-fusion frequency (CFF) has been used in clinical studies as a measure of visual fatigue. We examine the correlation between CFF and subjective reports of visual fatigue in a group of symptomatic computer users, to consider whether CFF may be used as a surrogate measure of visual fatigue symptoms. METHODS: We analysed data from a previous randomised controlled trial. One hundred and twenty adults, diagnosed with computer vision syndrome, had CFF and visual fatigue symptoms quantified before and after a visually demanding 2-h computer task. Symptoms were assessed using a questionnaire with nine subcomponents that summed to a total score of 900. CFF was measured using a two-interval forced-choice method, with the flicker rate altered by a computer-controlled staircase procedure. For our primary analysis, we determined Spearman correlation coefficients between post-task symptom scores and CFF, and between change from baseline symptom scores and CFF. We also used a bootstrap procedure to consider whether symptom score subcomponents were significantly (Bonferroni-corrected) different from overall scores with regard to their correlations with CFF. RESULTS: Although visual fatigue symptom scores altered significantly post-task (mean change: 92 units; 95% confidence interval [CI]: 11 to 122), CFF did not (mean change -0.7 Hz; 95% CI: -1.7 to 0.3). There was no significant correlation between overall symptom scores and CFF, either for the post-task (r = -0.13; 95% CI: -0.31 to 0.05) or the change from baseline (r = -0.18; 95% CI: -0.35 to 0.01) analysis. Subcomponents of the symptom questionnaire did not show a significant correlation with CFF, either for the post-task or the change from baseline analysis. CONCLUSIONS: We find that CFF is not a useful surrogate for symptoms of visual fatigue, given its low correlation with scores on a visual fatigue symptom questionnaire.
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    Endomembranes promote chromosome missegregation by ensheathing misaligned chromosomes
    Ferrandiz, N ; Downie, L ; Starling, GP ; Royle, SJ (ROCKEFELLER UNIV PRESS, 2022-05-05)
    Errors in mitosis that cause chromosome missegregation lead to aneuploidy and micronucleus formation, which are associated with cancer. Accurate segregation requires the alignment of all chromosomes by the mitotic spindle at the metaphase plate, and any misalignment must be corrected before anaphase is triggered. The spindle is situated in a membrane-free "exclusion zone"; beyond this zone, endomembranes (mainly endoplasmic reticulum) are densely packed. We investigated what happens to misaligned chromosomes localized beyond the exclusion zone. Here we show that such chromosomes become ensheathed in multiple layers of endomembranes. Chromosome ensheathing delays mitosis and increases the frequency of chromosome missegregation and micronucleus formation. We use an induced organelle relocalization strategy in live cells to show that clearance of endomembranes allows for the rescue of chromosomes that were destined for missegregation. Our findings indicate that endomembranes promote the missegregation of misaligned chromosomes that are outside the exclusion zone and therefore constitute a risk factor for aneuploidy.
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    Neuroimmune crosstalk in the cornea: The role of immune cells in corneal nerve maintenance during homeostasis and inflammation
    Wu, M ; Hill, LJ ; Downie, LE ; Chinnery, HR (PERGAMON-ELSEVIER SCIENCE LTD, 2022-11)
    In the cornea, resident immune cells are in close proximity to sensory nerves, consistent with their important roles in the maintenance of nerves in both homeostasis and inflammation. Using in vivo confocal microscopy in humans, and ex vivo immunostaining and fluorescent reporter mice to visualize corneal sensory nerves and immune cells, remarkable progress has been made to advance our understanding of the physical and functional interactions between corneal nerves and immune cells. In this review, we summarize and discuss recent studies relating to corneal immune cells and sensory nerves, and their interactions in health and disease. In particular, we consider how disrupted corneal nerve axons can induce immune cell activity, including in dendritic cells, macrophages and other infiltrating cells, directly and/or indirectly by releasing neuropeptides such as substance P and calcitonin gene-related peptide. We summarize growing evidence that the role of corneal intraepithelial immune cells is likely different in corneal wound healing versus other inflammatory-dominated conditions. The role of different types of macrophages is also discussed, including how stromal macrophages with anti-inflammatory phenotypes communicate with corneal nerves to provide neuroprotection, while macrophages with pro-inflammatory phenotypes, along with other infiltrating cells including neutrophils and CD4+ T cells, can be inhibitory to corneal re-innervation. Finally, this review considers the bidirectional interactions between corneal immune cells and corneal nerves, and how leveraging this interaction could represent a potential therapeutic approach for corneal neuropathy.